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Biomedical subjects

M Dennis

Publications and source records attributed to M Dennis.

At least 19 recordsLinked to original sources
PubMed1992

Atrial fibrillation and stroke: prevalence in different types of stroke and influence on early and long term prognosis (Oxfordshire community stroke project)

OBJECTIVE: To determine in patients with first ever stroke whether atrial fibrillation influences clinical features, the need to perform computed tomography, and prognosis. DESIGN: Observational cohort study with maximum follow up of 6.5 years. SETTING: Primary care, based on 10 general practices in urban and rural Oxfordshire. SUBJECTS: Consecutive series of 675 patients with first ever stroke registered in the Oxfordshire community stroke project. MAIN OUTCOME MEASURES: Prevalence of atrial fibrillation by type of stroke; effect of atrial fibrillation on case fatality rate and risk of recurrent stroke, vascular death, and death from all causes. RESULTS: Prevalence of atrial fibrillation was 17% (95% confidence interval 14% to 20%) for all stroke types (115/675), 18% (15% to 21%) for cerebral infarction (97/545), 11% (4% to 11%) for primary intercerebral haemorrhage (7/66), and 0% (0 to 11%) for subarachnoid haemorrhage (0/33). For patients with cerebral infarction the 30 day case fatality rate was significantly higher with atrial fibrillation (23%) than with sinus rhythm (8%); the risk of early recurrent stroke (within 30 days) was 1% with atrial fibrillation and 4% with sinus rhythm. In patients who survived at least 30 days the average annual risk of recurrent stroke was 8.2% (5.9% to 10.9%) with sinus rhythm and 11% (6.0% to 17.3%) with atrial fibrillation. CONCLUSIONS: After a first stroke atrial fibrillation was not associated with a definite excess risk of recurrent stroke, either within 30 days or within the first few years. Survivors with and without atrial fibrillation had a clinically important absolute risk of further serious vascular events.

Aged↗
PubMed1992

New nonpeptide angiotensin II receptor antagonists. 2. Synthesis, biological properties, and structure-activity relationships of 2-alkyl-4-(biphenylylmethoxy)quinoline derivatives.

A novel series of nonpeptidic angiotensin II (AII) receptor antagonists is reported, derived from linkage of the biphenylcarboxylic acid or biphenylyltetrazole moiety found in previously described antagonists via a methyleneoxy chain to the 4-position of a 2-alkyl quinoline. When evaluated in an in vitro binding assay using a guinea pig adrenal membrane preparation, compounds in this series generally gave IC50 values in the range 0.01-1 microM. Structure-activity studies showed the quinoline nitrogen atom and a short alkyl chain at the quinoline 2-position to be essential for receptor binding. On intravenous administration in a normotensive rat model, the more potent compounds inhibited the AII-induced pressor response with ED50 values in the range 0.1-2.0 mg/kg. One of the compounds, 2-ethyl-4-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methoxy]quinoline (5g), demonstrated good oral activity in two rat models. At doses in the range 1-10 mg/kg in AII-infused, normotensive rats, the compound exhibited a dose-related inhibition of the pressor response with a good duration of action at the higher doses. In a renal hypertensive rat model, compound 5g showed a rapid and sustained lowering of blood pressure at a dose of 5 mg/kg. On the basis of its profile, this compound, designated ICI D8731, has been selected for clinical evaluation.

Angiotensin II↗
PubMed1992

Agonist-modulated palmitoylation of beta 2-adrenergic receptor in Sf9 cells.

The palmitoylation of the human beta 2-adrenergic receptor (beta 2-AR) was studied in recombinant baculovirus-infected insect Sf9 cells. At 48 h post-infection, a high level expression of an epitope-tagged beta 2-AR (10-25 pmol/mg protein) was detected by [125I]iodocyanopindolol ([125I]CYP) binding assays. The identity of the receptor was confirmed both by photoaffinity labeling and immunoblotting. The fusion receptor displayed typical beta 2-AR pharmacological properties and conferred a beta-adrenergic sensitive adenylyl cyclase activity to the Sf9 cells. Moreover, exposure of the Sf9 cells to the beta-adrenergic agonist isoproterenol induced a rapid desensitization of the receptor-stimulated adenylyl cyclase activity. Purification of the epitope-tagged beta 2-AR by immunoprecipitation as well as by alprenolol-Sepharose affinity chromatography revealed that the receptor is covalently modified with palmitic acid in the insect cells as is observed in mammalian cells. In addition, short-term incubation of the cells with isoproterenol led to a specific increase in the incorporation of [3H]palmitate in the receptor, consistent with a rapid agonist-modulated turnover of the beta 2-AR-attached palmitic acid. These results suggest that agonist-mediated regulation of beta 2-AR post-translational palmitoylation could represent an other regulatory process for G protein-coupled receptors.

Affinity Labels↗
PubMed1992

Baculovirus expression of mammalian G protein alpha subunits.

Complementary DNAs encoding three subtypes of the alpha subunit (alpha i-1, alpha o and alpha s) of rat guanyl nucleotide regulatory proteins were used to construct recombinant baculoviruses which direct high-level expression of the corresponding proteins in cultured Sf9 insect cells. The expressed proteins were recognized by polyclonal antisera specific for the different alpha chains, and co-migrated with the native proteins from rat brain membranes in immunoblotting analyses. Soluble and particulate forms of all three immunoreactive alpha chains were observed following ultracentrifugation of cell lysates. Biosynthetic radiolabelling of infected cells with [35S]methionine or [3H]myristate showed that both soluble and particulate forms of alpha i-1 and alpha o were myristoylated; in contrast, alpha s did not incorporate myristate. The soluble fractions from cells expressing alpha chains showed high levels of GTP-binding activity over that observed in uninfected cells, or in cells infected with wild-type virus. The peak expression levels observed at 72 h post-infection were highest for alpha o at ca. 400 pmol of GTP-gamma-35S/mg protein, or roughly 2% of the total soluble protein. The results of this work show that the baculovirus system can be employed for high-level production of mammalian G protein alpha chains which retain GTP-binding activity and are appropriately modified by myristoylation.

Animals↗
PubMed1992

A cobalt-porphyrin enzyme converts a fatty aldehyde to a hydrocarbon and CO.

The final step in hydrocarbon biosynthesis involves loss of CO from a fatty aldehyde. This decarbonylation is catalyzed by microsomes from Botyrococcus braunii. Among the several detergents tested for solubilizing the decarbonylase, octyl beta-glucoside (0.1%) was found to be the most effective and released 65% of the enzyme activity in soluble form. FPLC of the solubilized enzyme preparation with Superose 6 followed by ion-exchange FPLC with Mono Q resulted in 200-fold increase in specific activity with 7% recovery. The purified enzyme released nearly 1 mol of CO for each mol of hydrocarbon. SDS/PAGE of the enzyme preparation showed two protein bands of equal intensity at 66 and 55 kDa. The absorption spectrum of the enzyme with bands at 410 nm, 425 nm, 580 nm, and 620 nm suggests the presence of a porphyrin. Electron microprobe analysis revealed that the enzyme contained Co. Purification of the decarbonylase from B. braunii grown in 57CoCl2 showed that 57Co coeluted with the decarbonylase. These results suggest that the enzyme contains Co that might be part of a Co-porphyrin, although a corrin structure cannot be ruled out. Co-protoporphyrin IX itself caused decarbonylation of octadecanal at 60 degrees C, whereas the metal ion or protoporphyrin alone, or several other metal porphyrins, did not cause decarbonylation. These results strongly suggest that biosynthesis of hydrocarbons is effected by a microsomal Co-porphyrin-containing enzyme that catalyzes decarbonylation of aldehydes and, thus, reveal a biological function for Co in plants.

Aldehyde-Lyases↗
PubMed1992

Stroke services.

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Cerebrovascular Disorders↗
PubMed1992

Intrarectal challenge of macaques vaccinated with formalin-inactivated simian immunodeficiency virus.

Macaques can be protected from intravenous infection with simian immunodeficiency virus (SIV) by vaccination with chemically inactivated virus. However, protection against infection via a mucosal surface has not been demonstrated. We vaccinated four rhesus macaques with formalin-inactivated SIV given intramuscularly. These monkeys, which had remained virus free for 10 months after intravenous challenge with SIV, were given a further dose of vaccine and together with four unvaccinated controls were challenged intrarectally with SIV. Subsequently, virus was isolated from all control animals on five successive occasions, but the vaccinated animals remained free of virus. Proviral DNA could not be detected in peripheral blood mononuclear cells from the vaccinated animals. Preliminary data indicate that vaccinated animals make a local antibody response.

AIDS Vaccines↗
PubMed1992

Diurnal variation in incidence of stroke: Oxfordshire community stroke project.

OBJECTIVE: To determine whether diurnal variation occurs in the onset of stroke. DESIGN: Community based study over four years. SETTING: Oxfordshire, United Kingdom. SUBJECTS: 105,000 people, of whom 675 had a first ever stroke. 545 had a cerebral infarction, 66 had primary intracerebral haemorrhage, 33 had subarachnoid haemorrhage, and in 31 the type of stroke was not known. MAIN OUTCOME MEASURES: Time of stroke and degree of activity at onset. RESULTS: In the 578 patients for whom it was known whether onset occurred while asleep or awake, the proportion with onset during sleep was 25% (135/545) for cerebral infarction, 17% (11/66) for primary intracerebral haemorrhage, and 0% (0/33) for subarachnoid haemorrhage. This difference persisted if patients in whom it was not known whether they were asleep or awake at onset were classed as asleep. For all stroke types together there was a significant (chi 2 = 218.7, p less than 0.001) diurnal variation with a morning peak between 0800 and 1000, which persisted even after allowing for strokes first noted on waking by redistributing the hour of onset through the preceding eight hours (chi 2 = 47, p less than 0.001). A significant diurnal variation was also found in the onset of cerebral infarction (peak 0800-1000, chi 2 = 208.4, p less than 0.001). Fewer patients had other forms of stroke and the diurnal variations for primary intracerebral haemorrhage (peak 1000-1200) and subarachnoid haemorrhage (peaks 0800-1000 and 1800-2000) were not significant. There seemed to be a second smaller peak for all types of stroke. CONCLUSIONS: All types of stroke are most likely to occur after waking in the morning. The cause of the circadian variation requires further study.

Cerebral Hemorrhage↗
PubMed1992

Brain tumors in children and adolescents--III. Effects of radiation and hormone status on intelligence and on working, associative and serial-order memory.

The effects on intelligence and memory of two post-surgical conditions (radiation treatment, hormone deficiency and supplementation) were explored in 46 children and adolescents with tumors in a variety of brain sites. Verbal intelligence, but not non-verbal intelligence, varied positively with age at radiation treatment. Memory for word meanings was unrelated to either radiation history or to hormone status. Severe deficits in serial position memory occurred with impaired hormone function and an older age at tumor onset. Severe deficits in working memory were associated with a history of radiation and a principal tumor site that involved thalamic/epithalamic brain regions. Radiation treatment and hormone status affect later cognitive function in children and adolescents with brain tumors. Although the greater vulnerability of the verbal intelligence of the younger radiated child and the serial order memory of the child with later tumor onset and hormone disturbances remain to be explained, and although the form of the relationship between radiation and tumor site is not fully understood, the data highlight the need to consider the cognitive consequences of pediatric brain tumors according to a set of markers that include maturational rate, hormone status, radiation history, and principal site of the tumor.

Adolescent↗
PubMed1992

Reading in children and adolescents after early onset hydrocephalus and in normally developing age peers: phonological analysis, word recognition, word comprehension, and passage comprehension skill.

Compared 50 children with early hydrocephalus, tested between the ages of 6 and 15 years, and their 51 age- and education-matched controls on 4 reading skills. Hydrocephalus and control groups did not differ in the ability to recognize words or to use phonological skills to decode "pretend" words, although the hydrocephalus group was poorer than the controls in understanding real words and texts. When individual differences in word recognition ability were controlled, the hydrocephalus group remained poorer than the controls in understanding single words and passages of text. Word recognition and passage comprehension skills were more highly correlated in the control group than in the hydrocephalus group. The passage comprehension scores of the hydrocephalus group lagged behind their word recognition scores, even for those children of normal or better IQ. Although the factors related to proficient and deficient reading comprehension for children with early hydrocephalus require further study, the present data show that adequate levels of word recognition, at least as measured by accuracy, in these children coexist with a significant deficit in reading comprehension.

Adolescent↗
PubMed1992

Migraine aura without headache: transient ischaemic attack or not?

Patients with "migraine aura without headache" can be separated from those with transient ischaemic attacks (TIA) on the basis of the onset of symptoms, which is generally gradual and which spread or intensify over minutes or hours, and from the typical migrainous nature of their visual symptoms. Fifty cases were prospectively identified and these were compared with 50 age matched patients with a TIA. Surprisingly, there were no significant differences in the prevalence of vascular risk factors and diseases in the two groups although those with TIAs tended to have more. Only one patient with "migraine aura without headache" suffered a subsequent vascular event (a myocardial infarction). Three patients with TIAs had strokes and two others died from vascular disease. Although the results are not conclusive, they do suggest that patients with the clinical characteristics of "migraine aura without headache" have a low risk of subsequent vascular events, lower than those with TIAs, despite perhaps having similar prevalence of vascular risk factors. Although their risk factors should be treated, patients with "migraine aura without headache" should be reassured and not subjected to inappropriate and potentially hazardous investigations and treatment.

Adult↗
PubMed1991

Strategy for stroke.

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Cerebrovascular Disorders↗
PubMed1991

Vasocontractile muscarinic M1 receptors in cat cerebral arteries: pharmacological identification and detection of mRNA.

The nature of the muscarinic receptor subtype mediating the acetylcholine (ACh)-induced constriction of the cat middle cerebral artery was investigated in vitro by recording the smooth muscle isometric tension of precontracted endothelium-denuded arterial segments. The ability of selective (pirenzepine, UH-AH 371, AF-DX 116, methoctramine, AQ-RA 741, 4-diphenylacetoxy-N-methylpiperidine methiodide (4-DAMP) and hexahydro-sila-difenidol (HHSiD)) and non-selective (atropine) antagonists to inhibit the constriction elicited by ACh was estimated. In addition, using a subtype-specific ribonucleotide probe directed against mRNA encoding the human m1 (Hm1) muscarinic receptor, identification of the corresponding vascular receptor was undertaken in total RNA extracts from cat cerebral blood vessels. The potent inhibition of the ACh-induced constriction by M1 antagonists (pirenzepine and UH-AH 371; pA2 values respectively of 8.08 and 8.64), together with lower affinities of M2 (AF-DX 116; pA2 = 6.50, methoctramine; pA2 = 6.27 and AQ-RA 741; pA2 = 7.60) and M3 compounds (4-DAMP and HHSiD; with pA2 values of 8.85 and 7.76, respectively) strongly suggested the involvement of a pharmacological M1 receptor in this vasomotor response. Furthermore, Northern blot hybridization with the selective Hm1 ribonucleotide probe showed the presence of mRNA transcripts for this muscarinic receptor subtype in the cat cerebrovascular bed. The results indicate that muscarinic constriction in the feline cerebrovascular bed is mediated by a pharmacological M1 receptor subtype and that the corresponding m1 receptor mRNA is present in cat cerebral blood vessels. These findings clearly point to a role of M1 muscarinic receptors in cerebrovascular function.

Acetylcholine↗
PubMed1991

Classification and natural history of clinically identifiable subtypes of cerebral infarction.

We describe the incidence and natural history of four clinically identifiable subgroups of cerebral infarction in a community-based study of 675 patients with first-ever stroke. Of 543 patients with a cerebral infarct, 92 (17%) had large anterior circulation infarcts with both cortical and subcortical involvement (total anterior circulation infarcts, TACI); 185 (34%) had more restricted and predominantly cortical infarcts (partial anterior circulation infarcts, PACI); 129 (24%) had infarcts clearly associated with the vertebrobasilar arterial territory (posterior circulation infarcts, POCI); and 137 (25%) had infarcts confined to the territory of the deep perforating arteries (lacunar infarcts, LACI). There were striking differences in natural history between the groups. The TACI group had a negligible chance of good functional outcome and mortality was high. More than twice as many deaths were due to the complications of immobility than to direct neurological sequelae of the infarct. Patients in the PACI group were much more likely to have an early recurrent stroke than were patients in other groups. Those in the POCI group were at greater risk of a recurrent stroke later in the first year after the index event but had the best chance of a good functional outcome. Despite the small anatomical size of the infarcts in the LACI group, many patients remained substantially handicapped. The findings have important implications for the planning of stroke treatment trials and suggest that various therapies could be directed specifically at the subgroups.

Age Factors↗
PubMed1991

Brain tumors in children and adolescents--I. Effects on working, associative and serial-order memory of IQ, age at tumor onset and age of tumor.

Memory impairment was demonstrated in a sample of 46 children and adolescents with brain tumors. The overall distribution of memory scores was skewed positively; over half of the total number of test measures were in the lowest quarter of the score distribution; and more than three-quarters of the individual subjects had at least one memory score in the impaired range. Verbal intelligence accounted for less than one-quarter of the variance in memory scores. The type of memory impairment was analyzed in relation to various demographic and medical variables: age at onset of tumor symptoms, age or duration of tumor, sex, pre-tumor developmental disturbances, pre-tumor closed head injury, post-tumor anticonvulsant treatment and post-tumor epileptic seizures. The working memory task, in which each in a succession of heard words is stored in temporary memory long enough to be compared to or contrasted with incoming words, was unaffected by these variables, as was memory for semantically-based word-picture associations. Memory for the serial order of pictures that corresponded to heard words varied inversely with the age at tumor onset such that the later the onset, the lower the memory test performance.

Adolescent↗
PubMed1991

Brain tumors in children and adolescents--II. The neuroanatomy of deficits in working, associative and serial-order memory.

The neuroanatomy of memory deficits was studied in 46 children and adolescents with brain tumors. CT-scan reconstructions of 88 brain regions were coded with respect to tumor and related damage, and multiple regression procedures established patterns of brain damage predictive of memory deficits. Two forms of memory revealed non-overlapping focal neuroanatomical substrates: memory for the serial order of pictures that corresponded to heard words involved structures in the limbic system and hypothalamic-pituitary axis; whereas working memory, in which each of a succession of heard words is stored in temporary memory long enough to be compared to or contrasted with incoming words, involved the pineal-habenular region and the anterior and medial thalamic nuclei. Memory for semantically-based word-picture associations, in contrast, was unaffected by tumors in several subcortical brain regions. These data bear on current analyses of the neural substrates of associative and representational memory.

Adolescent↗
PubMed1991

Mood disorders in the year after first stroke.

An unselected community sample of 128 patients were studied over the 12 months after their first stroke, and compared with a control sample of subjects from the general population. Psychiatric status was assessed using the PSE and BDI. Symptoms of mood disorder were commoner in the stroke patients than the controls, but the differences were not substantial and had largely disappeared by 12 months. Psychiatric problems encountered included agoraphobia, social withdrawal, apathy and self-neglect, irritability and pathological emotionalism. While there was a high cumulative incidence of psychiatric disorder, little of it persisted: only two cases of major depression were present for the whole 12 months. We believe undue emphasis has been placed in the recent literature on major depression as a specific syndrome following stroke.

Adolescent↗